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1
Tindall, Donald J. "S1 Molecular Mechanisms of Prostate Cancer Cell Survival following Androgen Ablative Therapy." Japanese Journal of Urology 97, no. 2 (2006): 127. http://dx.doi.org/10.5980/jpnjurol.97.127_2.
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Cross, N. A., M. Papageorgiou, and C. L. Eaton. "Bone marrow stromal cells promote growth and survival of prostate cancer cells." Biochemical Society Transactions 35, no. 4 (July 20, 2007): 698–700. http://dx.doi.org/10.1042/bst0350698.
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Prostate cancers frequently metastasize to the skeleton, and it has been hypothesized that this environment selectively supports the growth of these tumours. Specifically there is strong evidence that interactions between tumour cells and BMSCs (bone marrow stromal cells) play a major role in supporting prostate cancer growth and survival in bone. Here, we examine factors shown to be secreted by BMSCs, such as IGFs (insulin-like growth factors) and IL-6 (interleukin 6), shown to promote prostate cancer cell proliferation and to potentially replace the requirement for androgens. In addition we discuss another factor produced by BMSCs, osteoprotegerin, which may promote tumour cell survival by suppressing the biological activity of the pro-apoptotic ligand TRAIL (tumour-necrosis-factor-related apoptosis-inducing ligand).
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Kashani, Kilbas, Yerlikaya, Gurkan, and Arisan. "Cisplatin and Paclitaxel Modulated the Cell Survival Potential of Prostate Cancer Cells." Proceedings 40, no. 1 (January 5, 2020): 42. http://dx.doi.org/10.3390/proceedings2019040042.
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Prostate cancer is the second common cause of death among men worldwide. In the treatment of prostate cancer, conventional chemotherapeutics are commonly used. The plant alkaloid Paclitaxel and platinum-based cisplatin are the most common chemotherapy drugs. The transcription factor p53 has a potential target in the regulation of cell response to DNA damage of prostate cancer. Although the effectiveness of these drugs on prostate cancer cell progression had been proved, the mechanistic action of these drugs on the progression of the disease is not detailed explained. In this study, we aim to examine the function of p53 overexpression in prostate cancer cell survival. Therefore, we treated wild type (wt) and p53 overexpressed PC3 (p53+) prostate cancer cells with cisplatin or paclitaxel. According to the MTT Cell Viability assay, cisplatin (12.5–25–50 µM) was found to be more effective decreasing PC3 and PC3 p53+ cell viability in a dose-dependent manner compared to paclitaxel (12.5–25–50 nM). Colony formation assay showed that treatment of cells with cisplatin or paclitaxel caused the loss of colony forming ability of PC3 and PC3 p53+ cells. In addition, the critical apoptotic markers Caspase-3 and Caspase-9 expressions were altered with cisplatin or paclitaxel treated PC3 wt and p53+ cells.
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LEE, E. C. Y., and M. TENNISWOOD. "PROGRAMMED CELL DEATH AND SURVIVAL PATHWAYS IN PROSTATE CANCER CELLS." Archives of Andrology 50, no. 1 (January 2004): 27–32. http://dx.doi.org/10.1080/01485010490250498.
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Salih, T., K. Aziz, S. Thiyagarajan, M. Armour, B. Shanmugam, J. Zeng, S. J. Adam, D. W. Felsher, T. L. DeWeese, and P. T. Tran. "Radiosensitization of MYC-overexpressing prostate cancer cells by statins." Journal of Clinical Oncology 29, no. 7_suppl (March 1, 2011): 26. http://dx.doi.org/10.1200/jco.2011.29.7_suppl.26.
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26 Background: Studies have shown a link between HMG-CoA reductase inhibitors (statins) and decreased cancer risk in various cancers including prostate cancer. Recent clinical studies have shown improved outcome for men on statin therapy receiving definitive radiation therapy compared to radiation therapy alone for prostate cancer. The oncogene Ras can be inhibited by statin treatment and in turn also result in targeted downregulation of Myc. Inactivation of Myc has been shown to induce tumor regression in transgenic mouse models of different cancers. Methods: Utilizing both in vitro and in vivo models, we studied in MYC over-expressing prostate cancer cells statin induced cytotoxicity and radiosensitization. We studied the effect of statin treatment with and without radiation treatment on in vitro cell death and clonogenic survival and correlated effects to levels of MYC and phospho-MYC. We constructed mutant cell lines to specifically examine the MYC-dependent effects of statins on prostate cancer cell cytotoxicity and radiosensitization. We performed similar studies in vivo using subcutaneous tumor grafts. Results: Statin treatment alone of prostate cancer cells resulted in increased cell death and decreased clonegenic survival. Statin treatment further sensitized prostate cancer cells to ionizing radiation as shown through colony formation assays. These cellular effects were associated with decreased levels of active MYC as confirmed by western and phospho-western analysis. Statin-induced cell death and decreased MYC levels could be rescued with the HMG-CoA bypass product mevalonate. Finally, flank tumor graft experiments demonstrated the ability of statins and radiation to delay tumor growth in vivo. Conclusions: Our preliminary data have implicated MYC as a potential critical target for the cytotoxic effects of statins on prostate cancer cells. The prevalence of MYC overexpression in human prostate cancers is as high as 80%. Thus the ability of statins to radiosensitize MYC overexpressing prostate cancer cells may provide a mechanistic explanation to the improved outcomes for men taking statins while on radiation therapy and now may afford us a molecular biomarker to examine this phenomenon in the clinic. No significant financial relationships to disclose.
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Mamouni, Kenza, Georgios Kallifatidis, and Bal L. Lokeshwar. "Targeting Mitochondrial Metabolism in Prostate Cancer with Triterpenoids." International Journal of Molecular Sciences 22, no. 5 (February 28, 2021): 2466. http://dx.doi.org/10.3390/ijms22052466.
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Metabolic reprogramming is a hallmark of malignancy. It implements profound metabolic changes to sustain cancer cell survival and proliferation. Although the Warburg effect is a common feature of metabolic reprogramming, recent studies have revealed that tumor cells also depend on mitochondrial metabolism. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is an attractive therapeutic strategy. However, the metabolic flexibility of cancer cells may enable the upregulation of compensatory pathways, such as glycolysis, to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of targeting both mitochondrial metabolism and glycolysis may help overcome such resistance mechanisms. Normal prostate epithelial cells have a distinct metabolism as they use glucose to sustain physiological citrate secretion. During the transformation process, prostate cancer cells consume citrate to mainly power oxidative phosphorylation and fuel lipogenesis. A growing number of studies have assessed the impact of triterpenoids on prostate cancer metabolism, underlining their ability to hit different metabolic targets. In this review, we critically assess the metabolic transformations occurring in prostate cancer cells. We will then address the opportunities and challenges in using triterpenoids as modulators of prostate cancer cell metabolism.
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Dariane, Charles, Sylvie Clairefond, Benjamin Péant, Laudine Communal, Zhe Thian, Véronique Ouellet, Dominique Trudel, et al. "High Keratin-7 Expression in Benign Peri-Tumoral Prostatic Glands Is Predictive of Bone Metastasis Onset and Prostate Cancer-Specific Mortality." Cancers 14, no. 7 (March 23, 2022): 1623. http://dx.doi.org/10.3390/cancers14071623.
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Background: New predictive biomarkers are needed to accurately predict metastasis-free survival (MFS) and cancer-specific survival (CSS) in localized prostate cancer (PC). Keratin-7 (KRT7) overexpression has been associated with poor prognosis in several cancers and is described as a novel prostate progenitor marker in the mouse prostate. Methods: KRT7 expression was evaluated in prostatic cell lines and in human tissue by immunohistochemistry (IHC, on advanced PC, n = 91) and immunofluorescence (IF, on localized PC, n = 285). The KRT7 mean fluorescence intensity (MFI) was quantified in different compartments by digital analysis and correlated to clinical endpoints in the localized PC cohort. Results: KRT7 is expressed in prostatic cell lines and found in the basal and supra-basal compartment from healthy prostatic glands and benign peri-tumoral glands from localized PC. The KRT7 staining is lost in luminal cells from localized tumors and found as an aberrant sporadic staining (2.2%) in advanced PC. In the localized PC cohort, high KRT7 MFI above the 80th percentile in the basal compartment was significantly and independently correlated with MFS and CSS, and with hypertrophic basal cell phenotype. Conclusion: High KRT7 expression in benign glands is an independent biomarker of MFS and CSS, and its expression is lost in tumoral cells. These results require further validation on larger cohorts.
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Jähnisch, Hanka, Susanne Füssel, Andrea Kiessling, Rebekka Wehner, Stefan Zastrow, Michael Bachmann, Ernst Peter Rieber, Manfred P. Wirth, and Marc Schmitz. "Dendritic Cell-Based Immunotherapy for Prostate Cancer." Clinical and Developmental Immunology 2010 (2010): 1–8. http://dx.doi.org/10.1155/2010/517493.
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Dendritic cells (DCs) are professional antigen-presenting cells (APCs), which display an extraordinary capacity to induce, sustain, and regulate T-cell responses providing the opportunity of DC-based cancer vaccination strategies. Thus, clinical trials enrolling prostate cancer patients were conducted, which were based on the administration of DCs loaded with tumor-associated antigens. These clinical trials revealed that DC-based immunotherapeutic strategies represent safe and feasible concepts for the induction of immunological and clinical responses in prostate cancer patients. In this context, the administration of the vaccine sipuleucel-T consisting of autologous peripheral blood mononuclear cells including APCs, which were pre-exposedin vitroto the fusion protein PA2024, resulted in a prolonged overall survival among patients with metastatic castration-resistent prostate cancer. In April 2010, sipuleucel-T was approved by the United States Food and Drug Administration for prostate cancer therapy.
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Harris, Koran S., and Bethany A. Kerr. "Prostate Cancer Stem Cell Markers Drive Progression, Therapeutic Resistance, and Bone Metastasis." Stem Cells International 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/8629234.
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Metastatic or recurrent tumors are the primary cause of cancer-related death. For prostate cancer, patients diagnosed with local disease have a 99% 5-year survival rate; however, this 5-year survival rate drops to 28% in patients with metastatic disease. This dramatic decline in survival has driven interest in discovering new markers able to identify tumors likely to recur and in developing new methods to prevent metastases from occurring. Biomarker discovery for aggressive tumor cells includes attempts to identify cancer stem cells (CSCs). CSCs are defined as tumor cells capable of self-renewal and regenerating the entire tumor heterogeneity. Thus, it is hypothesized that CSCs may drive primary tumor aggressiveness, metastatic colonization, and therapeutic relapse. The ability to identify these cells in the primary tumor or circulation would provide prognostic information capable of driving prostate cancer treatment decisions. Further, the ability to target these CSCs could prevent tumor metastasis and relapse after therapy allowing for prostate cancer to finally be cured. Here, we will review potential CSC markers and highlight evidence that describes how cells expressing each marker may drive prostate cancer progression, metastatic colonization and growth, tumor recurrence, and resistance to treatment.
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Pulukuri, Sai MuraliKrishna, Christopher S. Gondi, Sajani S. Lakka, Aman Jutla, Norman Estes, Meena Gujrati, and Jasti S. Rao. "RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo." Journal of Biological Chemistry 280, no. 43 (August 26, 2005): 36529–40. http://dx.doi.org/10.1074/jbc.m503111200.
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The invasive ability of tumor cells plays a key role in prostate cancer metastasis and is a major cause of treatment failure. Urokinase plasminogen activator-(uPA) and its receptor (uPAR)-mediated signaling have been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study was undertaken to investigate the biological roles of uPA and uPAR in prostate cancer cell invasion and survival, and the potential of uPA and uPAR as targets for prostate cancer therapy. uPA and uPAR expression correlates with the metastatic potential of prostate cancer cells. Thus, therapies designed to inhibit uPA and uPAR expression would be beneficial. LNCaP, DU145, and PC3 are prostate cancer cell lines with low, moderate, and high metastatic potential, respectively, as demonstrated by their capacity to invade the extracellular matrix. In this study we utilized small hairpin RNAs (shRNAs), also referred to as small interfering RNAs, to target human uPA and uPAR. These small interfering RNA constructs significantly inhibited uPA and uPAR expression at both the mRNA and protein levels in the highly metastatic prostate cancer cell line PC3. Our data demonstrated that uPA-uPAR knockdown in PC3 cells resulted in a dramatic reduction of tumor cell invasion as indicated by a Matrigel invasion assay. Furthermore, simultaneous silencing of the genes for uPA and uPAR using a single plasmid construct expressing shRNAs for both uPA and uPAR significantly reduced cell viability and ultimately resulted in the induction of apoptotic cell death. RNA interference for uPA and uPAR also abrogated uPA-uPAR signaling to downstream target molecules such as ERK1/2 and Stat 3. In addition, our results demonstrated that intratumoral injection with the plasmid construct expressing shRNAs for uPA and uPAR almost completely inhibited established tumor growth and survival in an orthotopic mouse prostate cancer model. These findings uncovered evidence of a complex signaling network operating downstream of uPA-uPAR that actively advances tumor cell invasion, proliferation, and survival of prostate cancer cells. Thus, RNA interference-directed targeting of uPA and uPAR is a convenient and novel tool for studying the biological role of the uPA-uPAR system and raises the potential of its application for prostate cancer therapy.
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Molloy, Niamh, Danielle Read, and Adrienne Gorman. "Nerve Growth Factor in Cancer Cell Death and Survival." Cancers 3, no. 1 (February 1, 2011): 510–30. http://dx.doi.org/10.3390/cancers3010510.
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One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75NTR, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75NTR. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75NTR. This latter signaling through p75NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer.
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Liu, X. Shawn, Bing Song, Bennett D. Elzey, Timothy L. Ratliff, Stephen F. Konieczny, Liang Cheng, Nihal Ahmad, and Xiaoqi Liu. "Polo-like Kinase 1 Facilitates Loss of Pten Tumor Suppressor-induced Prostate Cancer Formation." Journal of Biological Chemistry 286, no. 41 (September 2, 2011): 35795–800. http://dx.doi.org/10.1074/jbc.c111.269050.
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Loss of the tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome 10) is thought to mediate the majority of prostate cancers, but the molecular mechanism remains elusive. In this study, we demonstrate that Pten-depleted cells suffer from mitotic stress and that nuclear function of Pten, but not its phosphatase activity, is required to reverse this stress phenotype. Further, depletion of Pten results in elevated expression of Polo-like kinase 1 (Plk1), a critical regulator of the cell cycle. We show that overexpression of Plk1 correlates with genetic inactivation of Pten during prostate neoplasia formation. Significantly, we find that elevated Plk1 is critical for Pten-depleted cells to adapt to mitotic stress for survival and that reintroduction of wild-type Pten into Pten-null prostate cancer cells reduces the survival dependence on Plk1. We further show that Plk1 confers the tumorigenic competence of Pten-deleted prostate cancer cells in a mouse xenograft model. These findings identify a role of Plk1 in facilitating loss of Pten-induced prostate cancer formation, which suggests that Plk1 might be a promising target for prostate cancer patients with inactivating Pten mutations.
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Shen, Gang, Jianchun Chen, Yongqiang Zhou, Zhenfan Wang, Zheng Ma, Chen Xu, and Minjun Jiang. "AZD5153 Inhibits Prostate Cancer Cell Growth in Vitro and in Vivo." Cellular Physiology and Biochemistry 50, no. 2 (2018): 798–809. http://dx.doi.org/10.1159/000494244.
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Backgrounds/Aims: Bromodomain-containing protein 4 (BRD4) overexpression participates in prostate cancer progression by enhancing the transcriptional activity and expression of several key oncogenes. AZD5153 is a novel BRD4 inhibitor. Methods: Prostate cancer cells were treated with AZD5153. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by [H3] DNA incorporation assay. Cell apoptosis was tested by caspase-3/-9 activity assay, Histone DNA ELISA assay, Annexin V FACS assay and TUNEL staining assay. Cell cycle progression was tested by propidium iodide (PI) FACS assay. Signaling was tested by Western blotting assay. The nude mice PC-3 xenograft model was applied to test AZD5153’s activity in vivo. Results: AZD5153 inhibited proliferation and survival of established and primary prostate cancer cells. AZD5153 induced apoptosis activation and cell cycle arrest in prostate cancer cells. AZD5153 was non-cytotoxic to the prostate epithelial cells. AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, FOSL1 and CDK4) in PC-3 and primary prostate cancer cells. Further studies show that AKT could be the primary resistance factor of AZD5153. Pharmacological inhibition or genetic depletion of AKT induced BRD4 downregulation, sensitizing AZD5153-induced cytotoxicity in PC-3 cells. In vivo, AZD5153 oral administration inhibited PC-3 xenograft tumor growth in nude mice. Its anti-tumor activity was further enhanced with co-treatment of the AKT specific inhibitor MK-2206. Conclusion: Together, our results indicate a promising therapeutic value of the novel BRD4 inhibitor AZD5153 against prostate cancer cells.
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Liao, Chun-Peng, Leng-Ying Chen, Andrea Luethy, Youngsoo Kim, Kian Kani, A. Robert MacLeod, and Mitchell E. Gross. "Androgen receptor in cancer-associated fibroblasts influences stemness in cancer cells." Endocrine-Related Cancer 24, no. 4 (April 2017): 157–70. http://dx.doi.org/10.1530/erc-16-0138.
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Androgen receptor (AR) regulation pathways are essential for supporting the growth and survival of prostate cancer cells. Recently, sub-populations of prostate cancer cells have been identified with stem cell features and are associated with the emergence of treatment-resistant prostate cancer. Here, we explored the function of AR in prostate cancer-associated fibroblasts (CAFs) relative to growth and stem cell-associated characteristics. CAFs were isolated from the murine cPten−/−L prostate cancer model and cultured with human prostate cancer epithelial (hPCa) cells. A murine-specific AR antisense oligonucleotide (ASO) was used to suppress the expression of AR in the CAF cells. CAFs express low, but significant levels of AR relative to fibroblasts derived from non-malignant tissue. CAFs promoted growth and colony formation of hPCa cells, which was attenuated by the suppression of AR expression. Surprisingly, AR-depleted CAFs promoted increased stem cell marker expression in hPCa cells. Interferon gamma (IFN-γ) and macrophage colony-stimulating factor (M-CSF) were increased in AR-depleted CAF cells and exhibited similar effects on stem cell marker expression as seen in the CAF co-culture systems. Clinically, elevated IFN-γ expression was found to correlate with histologic grade in primary prostate cancer samples. In summary, AR and androgen-dependent signaling are active in CAFs and exert significant effects on prostate cancer cells. IFN-γ and M-CSF are AR-regulated factors secreted by CAF cells, which promote the expression of stem cell markers in prostate cancer epithelial cells. Understanding how CAFs and other constituents of stromal tissue react to anti-cancer therapies may provide insight into the development and progression of prostate cancer.
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Virolle, Thierry, Anja Krones-Herzig, Veronique Baron, Giorgia De Gregorio, Eileen D. Adamson, and Dan Mercola. "Egr1 Promotes Growth and Survival of Prostate Cancer Cells." Journal of Biological Chemistry 278, no. 14 (January 29, 2003): 11802–10. http://dx.doi.org/10.1074/jbc.m210279200.
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Liou, Geou-Yarh. "Inflammatory Cytokine Signaling during Development of Pancreatic and Prostate Cancers." Journal of Immunology Research 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/7979637.
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Inflammation is essential for many diseases including cancer. Activation and recruitment of immune cells during inflammation result in a cytokine- and chemokine-enriched cell environment, which affects cancer development. Since each type of cancer has its unique tumor environment, effects of cytokines from different sources such as tumor-infiltrating immune cells, stromal cells, endothelial cells, and cancer cells on cancer development can be quite complex. In this review, how immune cells contribute to tumorigenesis of pancreatic and prostate cancers through their secreted cytokines is discussed. In addition, the cytokine signaling that tumor cells of pancreatic and prostate cancers utilize to benefit their own survival is delineated.
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Popov, S. V., N. V. Sturov, N. V. Vorobyev, and S. V. Khaidukov. "ROLE OF THE REGULATORY T CELLS IN PROGRESSION OF PROSTATE CANCER." Medical Immunology (Russia) 21, no. 4 (October 29, 2019): 587–94. http://dx.doi.org/10.15789/1563-0625-2019-4-587-594.
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The existing data on regulatory T cells (Tregs) in prostate cancer suggest that these cells may penetrate the prostate gland malignant tissue, suppressing antitumor immune response, thus promoting aggressive clinical course and low survival of the cancer patients. Evaluation of T cell subpopulations from the tumor microenvironment has shown that the number of CD4+Tregs is associated with inferior clinical prognosis. In particular, each additional CD4+Treg cell has been shown to cause a statistically significant increase in prostate cancer mortality by 12%, regardless of other clinical factors. There are several possible explanations for the increased infiltration of prostate cancer tissue with regulatory T cells. Firstly, malignant cells or tumor-associated macrophages are capable of secreting chemokine CCL22, which has an affinity for the CCR4 receptor expressed on Treg cells. Secondly, cytokines secreted by prostate tumors, such as TGF-β, may regulate the FoxP3 expression, thus expanding the Treg population. TGF-β, in turn, is a multifunctional cytokine that promotes survival and proliferation of transformed cells, including prostate epithelium, as evidenced by increased amounts in the patients with metastatic disease.
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Vanneste, Domien, Jens Staal, Mira Haegman, Yasmine Driege, Marieke Carels, Elien Van Nuffel, Pieter De Bleser, Yvan Saeys, Rudi Beyaert, and Inna S. Afonina. "CARD14 Signalling Ensures Cell Survival and Cancer Associated Gene Expression in Prostate Cancer Cells." Biomedicines 10, no. 8 (August 18, 2022): 2008. http://dx.doi.org/10.3390/biomedicines10082008.
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Prostate cancer (PCa) is one of the most common cancer types in men and represents an increasing global problem due to the modern Western lifestyle. The signalling adapter protein CARD14 is specifically expressed in epithelial cells, where it has been shown to mediate NF-κB signalling, but a role for CARD14 in carcinoma has not yet been described. By analysing existing cancer databases, we found that CARD14 overexpression strongly correlates with aggressive PCa in human patients. Moreover, we showed that CARD14 is overexpressed in the LNCaP PCa cell line and that knockdown of CARD14 severely reduces LNCaP cell survival. Similarly, knockdown of BCL10 and MALT1, which are known to form a signalling complex with CARD14, also induced LNCaP cell death. MALT1 is a paracaspase that mediates downstream signalling by acting as a scaffold, as well as a protease. Recent studies have already indicated a role for the scaffold function of MALT1 in PCa cell growth. Here, we also demonstrated constitutive MALT1 proteolytic activity in several PCa cell lines, leading to cleavage of A20 and CYLD. Inhibition of MALT1 protease activity did not affect PCa cell survival nor activation of NF-κB and JNK signalling, but reduced expression of cancer-associated genes, including the cytokine IL-6. Taken together, our results revealed a novel role for CARD14-induced signalling in regulating PCa cell survival and gene expression. The epithelial cell type-specific expression of CARD14 may offer novel opportunities for more specific therapeutic targeting approaches in PCa.
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Doonan, Bently P., Shereen Amria, Jennifer R. Bethard, Narendra L. Banik, Jessica D. Hathaway-Schrader, and Azizul Haque. "Peptide Modification Diminishes HLA Class II-restricted CD4+ T Cell Recognition of Prostate Cancer Cells." International Journal of Molecular Sciences 23, no. 23 (December 3, 2022): 15234. http://dx.doi.org/10.3390/ijms232315234.
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Prostate cancer poses an ongoing problem in the western world accounting for significant morbidity and mortality in the male population. Current therapy options are effective in treating most prostate cancer patients, but a significant number of patients progress beyond a manageable disease. For these patients, immunotherapy has emerged as a real option in the treatment of the late-stage metastatic disease. Unfortunately, even the most successful immunotherapy strategies have only led to a four-month increase in survival. One issue responsible for the shortcomings in cancer immunotherapy is the inability to stimulate helper CD4+ T cells via the HLA class II pathway to generate a potent antitumor response. Obstacles to proper HLA class II stimulation in prostate cancer vaccine design include the lack of detectable class II proteins in prostate tumors and the absence of defined class II specific prostate tumor antigens. Here, for the first time, we show that the insertion of a lysosomal thiol reductase (GILT) into prostate cancer cells directly enhances HLA class II antigen processing and results in increased CD4+ T cell activation by prostate cancer cells. We also show that GILT insertion does not alter the expression of prostate-specific membrane antigen (PSMA), an important target in prostate cancer vaccine strategies. Our study suggests that GILT expression enhances the presentation of the immunodominant PSMA459 epitope via the HLA class II pathway. Biochemical analysis showed that the PSMA459 peptide was cysteinylated under a normal physiologic concentration of cystine, and this cysteinylated form of PSMA459 inhibited T cell activation. Taken together, these results suggest that GILT has the potential to increase HLA class II Ag presentation and CD4+ T cell recognition of prostate cancer cells, and GILT-expressing prostate cancer cells could be used in designing cell therapy and/or vaccines against prostate cancer.
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Sun, Ming, Donghua Geng, Shuqiang Li, Zhaofu Chen, and Wenyan Zhao. "LncRNA PART1 modulates toll-like receptor pathways to influence cell proliferation and apoptosis in prostate cancer cells." Biological Chemistry 399, no. 4 (March 28, 2018): 387–95. http://dx.doi.org/10.1515/hsz-2017-0255.
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AbstractWe investigated thoroughly the effect of lncRNA PART1 on prostate cancer cells proliferation and apoptosis, through regulating toll-like receptor (TLR) pathways. LncRNA PART1 expression was also examined by quantitative real-time polymerase chain reactions (qRT-PCR) in human tissues and the cells lines LNCaP and PC3. After transfection with si-PART1 or control constructs, the cell viability was measured by MTS and colony formation assays. In addition, the apoptosis rate of the prostate cancer cells was validated by TUNEL staining. Relationships between lncRNA PART1 expression and TLR pathway genes were demonstrated by qRT-PCR and Western blotting. High levels of lncRNA PART1 expression were correlated with advanced cancer stage and predication of poor survival. LncRNA PART1 levels was increased in PCa cells treated with 5α-dihydrotestosterone (DHT), confirming PART1 was directly induced by androgen. Moreover, down-regulation of lncRNA PART1 inhibited prostate cancer cell proliferation and accelerated cell apoptosis. In addition, lncRNA PART1 induced downstream genes expression in TLR pathways includingTLR3,TNFSF10andCXCL13to further influence prostate cancer cells, indicating its carcinogenesis on prostate cancer. LncRNA PART1 promoted cell proliferation ability and apoptosis via the inhibition of TLR pathways in prostate cancer. LncRNA PART1 could hence be considered as a new target in the treatment of prostate cancer.
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Groen, Levi, Viktor Yurevych, Harshitha Ramu, Johnny Chen, Lianne Steenge, Sabrina Boer, Renske Kuiper, et al. "The Androgen Regulated lncRNA NAALADL2-AS2 Promotes Tumor Cell Survival in Prostate Cancer." Non-Coding RNA 8, no. 6 (December 1, 2022): 81. http://dx.doi.org/10.3390/ncrna8060081.
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Castration resistance is the leading cause of death in men with prostate cancer. Recent studies indicate long noncoding RNAs (lncRNAs) to be important drivers of therapy resistance. The aim of this study was to identify differentially expressed lncRNAs in castration-resistant prostate cancer (CRPC) and to functionally characterize them in vitro. Tumor-derived RNA-sequencing data were used to quantify and compare the expression of 11,469 lncRNAs in benign, primary prostate cancer, and CRPC samples. CRPC-associated lncRNAs were selected for semi-quantitative PCR validation on 68 surgical tumor specimens. In vitro functional studies were performed by antisense-oligonucleotide-mediated lncRNA knockdown in hormone-sensitive prostate cancer (HSPC) and CRPC cell line models. Subsequently, cell proliferation, apoptosis, cell cycle, transcriptome and pathway analyses were performed using the appropriate assays. Transcriptome analysis of a prostate cancer tumor specimens unveiled NAALADL2-AS2 as a novel CRPC-upregulated lncRNA. The expression of NAALADL2-AS2 was found to be particularly high in HSPC in vitro models and to increase under androgen deprived conditions. NAALADL2-AS2 knockdown decreased cell viability and increased caspase activity and apoptotic cells. Cellular fractionization and RNA fluorescent in situ hybridization identified NAALADL2-AS2 as a nuclear transcript. Transcriptome and pathway analyses revealed that NAALADL2-AS2 modulates the expression of genes involved with cell cycle control and glycogen metabolism. We hypothesize that the nuclear lncRNA, NAALADL2-AS2, functions as a pro-survival signal in prostate cancer cells under pressure of targeted hormone therapy.
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Den, Robert Benjamin, Steve Ciment, Ankur Sharma, Hestia Mellert, Steven McMahon, Adam Dicker, and Karen E. Knudsen. "Differential response of prostate cancer cells to ionizing radiation: The RB status." Journal of Clinical Oncology 30, no. 5_suppl (February 10, 2012): 106. http://dx.doi.org/10.1200/jco.2012.30.5_suppl.106.
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106 Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. The retinoblastoma tumor suppressor protein, RB, plays a critical role in cell cycle regulation and loss of RB has been observed in 25-30% of prostate cancers. We have previously shown that RB loss results in a castrate resistant phenotype, however the consequences of RB status with regard to radiation response are unknown. We hypothesized that RB loss would downregulate the G1-S cell cycle checkpoint arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to ionizing radiation. Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42, 22Rv1 cells; stable knockdown of RB using shRNA). Gamma H2AX assays were used to quantitate DNA damage and PARP cleavage and Caspase 3 were used to quantitate apoptosis. FACS analysis with BrdU was used to assess the cell cycle. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts. Results: We observed that loss of RB increased radioresponsiveness in both transient and clonogenic cell survival assays in both hormone sensitive and castrate resistant cell lines (p<0.05). Cell death was not mediated through increased apoptosis nor was perturbations in cell cycle noted. However, loss of RB effected DNA repair as measured by gamma H2AX staining as well as cellular senescence. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p<0.05). Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. The underlying mechanism appears to be related to DNA damage repair and cellular senescence.
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Bjerknes, Christian, Bomi Framroze, Crawford Currie, Caroline Hild Hakvåg Pettersen, Karol Axcrona, and Erland Hermansen. "Salmon Protein Hydrolysate Potentiates the Growth Inhibitory Effect of Bicalutamide on Human Prostate Cancer Cell Lines LNCaP and PC3 by Modulating Iron Homeostasis." Marine Drugs 20, no. 4 (March 28, 2022): 228. http://dx.doi.org/10.3390/md20040228.
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Prostate cancer is a common cause of cancer death in men. In advanced stages of prostate cancer, androgen deprivation therapy (ADT) is initiated. Despite ADT, prostate cancers invariably progress to become androgen independent. A growing body of evidence implicates iron dysmetabolism in prostate cancer progression. A bioactive peptide-rich salmon protein hydrolysate (SPH) has previously been demonstrated to modulate iron homeostatic mechanisms. In the present study, the anticancer effect of SPH and bicalutamide co-treatment on LNCaP and PC3 prostate cancer cell proliferation was investigated. Our results found that SPH potentiates the anti-proliferative effect of bicalutamide in a dose-dependent manner for both cell lines. In the presence of 160 µg/mL SPH, co-treatment with 1.0 µM bicalutamide decreased LNCaP cells’ relative colony survival from 25% (1.0 µM bicalutamide monotreatment) to 2% after culturing for 12 days. For PC3 cells, the relative colony survival diminished from 52% (10.0 µM bicalutamide) to 32% at an SPH concentration of 160 µg/mL. Gene expression profiling, employing quantitative real-time PCR, revealed that the inhibitory effects were related to significant FTH1 up-regulation with a concomitant TFRC down-regulation. In conclusion, our results provide in vitro evidence that SPH potentiates the growth inhibitory effect of bicalutamide on prostate cancer cells by modulating iron homeostasis mechanisms.
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Guan, Wei, Fan Li, Zhenyu Zhao, Zongbiao Zhang, Junhui Hu, and Yan Zhang. "Tumor-Associated Macrophage Promotes the Survival of Cancer Cells upon Docetaxel Chemotherapy via the CSF1/CSF1R–CXCL12/CXCR4 Axis in Castration-Resistant Prostate Cancer." Genes 12, no. 5 (May 19, 2021): 773. http://dx.doi.org/10.3390/genes12050773.
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Castration-resistant prostate cancer (CRPC) is an advanced stage of prostate cancer that can progress rapidly even in patients treated with castration. Previously, we found that tumor-associated macrophages (TAM) can be recruited by CSF-1 secreted by docetaxel-treated prostate cancer cells and promote the survival of cancer cells in response to chemotherapy. The inhibition of CSF-1R can impede this effect and significantly prolong survival in xenograft mice. However, the actual mechanism of how TAM improves cancer cell survival still remains elusive and controversial. Here, for the first time, we found that the enhanced survival of cancer cells achieved by TAM was mainly mediated by CXCR4 activation from the increased secretion of CXCL12 from CSF-1 activated TAM. This finding helps to clarify the mechanism of chemoresistance for second-line chemotherapy using docetaxel, facilitating the development of novel drugs to overcome immune tolerance in castration-resistant prostate cancer.
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Binder, Marley J., Scott McCoombe, Elizabeth D. Williams, Daniel R. McCulloch, and Alister C. Ward. "ADAMTS-15 Has a Tumor Suppressor Role in Prostate Cancer." Biomolecules 10, no. 5 (April 28, 2020): 682. http://dx.doi.org/10.3390/biom10050682.
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Extracellular matrix remodeling has emerged as an important factor in many cancers. Proteoglycans, including versican (VCAN), are regulated via cleavage by the proteolytic actions of A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 motif (ADAMTS) family members. Alterations in the balance between Proteoglycans and ADAMTS enzymes have been proposed to contribute to cancer progression. Here, we analyzed the expression of ADAMTS-15 in human prostate cancer, and investigated the effects of enforced expression in prostate cancer cell lines. ADAMTS-15 was found to be expressed in human prostate cancer biopsies with evidence of co-localization with VCAN and its bioactive cleavage fragment versikine. Enforced expression of ADAMTS-15, but not a catalytically-inactive version, decreased cell proliferation and migration of the ‘castrate-resistant’ PC3 prostate cancer cell line in vitro, with survival increased. Analysis of ‘androgen-responsive’ LNCaP prostate cancer cells in vivo in NOD/SCID mice revealed that ADAMTS-15 expression caused slower growing tumors, which resulted in increased survival. This was not observed in castrated mice or with cells expressing catalytically-inactive ADAMTS-15. Collectively, this research identifies the enzymatic function of ADAMTS-15 as having a tumor suppressor role in prostate cancer, possibly in concert with androgens, and that VCAN represents a likely key substrate, highlighting potential new options for the clinic.
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Montagner, Isabella Monia, Alessandro Penna, Giulio Fracasso, Debora Carpanese, Anna Dalla Pietà, Vito Barbieri, Gaia Zuccolotto, and Antonio Rosato. "Anti-PSMA CAR-Engineered NK-92 Cells: An Off-the-Shelf Cell Therapy for Prostate Cancer." Cells 9, no. 6 (June 2, 2020): 1382. http://dx.doi.org/10.3390/cells9061382.
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Prostate cancer (PCa) has become the most common cancer among males in Europe and the USA. Adoptive immunotherapy appears a promising strategy to control the advanced stages of the disease by specifically targeting the tumor, in particular through chimeric antigen receptor T (CAR-T) cell therapy. Despite the advancements of CAR-T technology in the treatment of hematological malignancies, solid tumors still represent a challenge. To overcome current limits, other cellular effectors than T lymphocytes are under study as possible candidates for CAR-engineered cancer immunotherapy. A novel approach involves the NK-92 cell line, which mediates strong cytotoxic responses against a variety of tumor cells but has no effect on non-malignant healthy counterparts. Here, we report a novel therapeutic approach against PCa based on engineering of NK-92 cells with a CAR recognizing the human prostate-specific membrane antigen (PSMA), which is overexpressed in prostatic neoplastic cells. More importantly, the potential utility of NK-92/CAR cells to treat PCa has not yet been explored. Upon CAR transduction, NK-92/CAR cells acquired high and specific lytic activity against PSMA-expressing prostate cancer cells in vitro, and also underwent degranulation and produced high levels of IFN-γ in response to antigen recognition. Lethal irradiation of the effectors, a safety measure requested for the clinical application of retargeted NK-92 cells, fully abrogated replication but did not impact on phenotype and short-term functionality. PSMA-specific recognition and antitumor activity were retained in vivo, as adoptive transfer of irradiated NK-92/CAR cells in prostate cancer-bearing mice restrained tumor growth and improved survival. Anti-PSMA CAR-modified NK-92 cells represent a universal, off-the-shelf, renewable, and cost-effective product endowed with relevant potentialities as a therapeutic approach for PCa immunotherapy.
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Lin, Hung-Yu, Yong-Shiou Lin, Shou-Ping Shih, Sung-Bau Lee, Mohamed El-Shazly, Ken-Ming Chang, Yu-Chen S. H. Yang, Yi-Lun Lee, and Mei-Chin Lu. "The Anti-Proliferative Activity of Secondary Metabolite from the Marine Streptomyces sp. against Prostate Cancer Cells." Life 11, no. 12 (December 16, 2021): 1414. http://dx.doi.org/10.3390/life11121414.
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Many active substances from marine organisms are produced by symbiotic microorganisms such as bacteria, fungi, and algae. Secondary metabolites from marine actinomycetes exhibited several biological activities and provided interesting drug leads. This study reported the isolation of Lu01-M, a secondary metabolite from the marine actinomycetes Streptomyces sp., with potent anti-proliferative activity against prostate cancers. Lu01-M blocked cell proliferation with IC50 values of 1.03 ± 0.31, 2.12 ± 0.38, 1.27 ± 0.25 μg/mL in human prostate cancer PC3, DU145, and LNCaP cells, respectively. Lu01-M induced cytotoxic activity through multiple mechanisms including cell apoptosis, necroptosis, autophagy, ER stress, and inhibiting colony formation and cell migration. Lu01-M induced cell cycle arrest at the G2/M phase and DNA damage. However, the activity of autophagy induced survival response in cancer cells. Our findings suggested that Lu01-M holds the potential to be developed as an anti-cancer agent against prostate cancers.
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Daaka, Yehia, and Ganesh V. Raj. "G protein-mediated survival of prostate cancer cells." European Urology Supplements 2, no. 6 (September 2003): 20. http://dx.doi.org/10.1016/s1569-9056(03)90399-x.
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Rivello, Francesca, Kinga Matuła, Aigars Piruska, Minke Smits, Niven Mehra, and Wilhelm T. S. Huck. "Probing single-cell metabolism reveals prognostic value of highly metabolically active circulating stromal cells in prostate cancer." Science Advances 6, no. 40 (September 2020): eaaz3849. http://dx.doi.org/10.1126/sciadv.aaz3849.
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Despite their important role in metastatic disease, no general method to detect circulating stromal cells (CStCs) exists. Here, we present the Metabolic Assay-Chip (MA-Chip) as a label-free, droplet-based microfluidic approach allowing single-cell extracellular pH measurement for the detection and isolation of highly metabolically active cells (hm-cells) from the tumor microenvironment. Single-cell mRNA-sequencing analysis of the hm-cells from metastatic prostate cancer patients revealed that approximately 10% were canonical EpCAM+ hm-CTCs, 3% were EpCAM− hm-CTCs with up-regulation of prostate-related genes, and 87% were hm-CStCs with profiles characteristic for cancer-associated fibroblasts, mesenchymal stem cells, and endothelial cells. Kaplan-Meier analysis shows that metastatic prostate cancer patients with more than five hm-cells have a significantly poorer survival probability than those with zero to five hm-cells. Thus, prevalence of hm-cells is a prognosticator of poor outcome in prostate cancer, and a potentially predictive and therapy response biomarker for agents cotargeting stromal components and preventing epithelial-to-mesenchymal transition.
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Qu, Jing-Jing, Lin-Lin Shi, Yan-Bing Wang, Jing Yan, Tian Shao, Xin-Qi Hao, Jia-Xiang Wang, Hong-Yu Zhang, Jun-Fang Gong, and Bing Song. "The Novel Function of Unsymmetrical Chiral CCN Pincer Nickel Complexes as Chemotherapeutic Agents Targeting Prostate Cancer Cells." Molecules 27, no. 10 (May 12, 2022): 3106. http://dx.doi.org/10.3390/molecules27103106.
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We report that the pincer nickel complexes display prostate cancer antitumor properties through inhibition of cell proliferation. Notably, they display better antitumor properties than cisplatin. Mechanistic studies reveal that these pincer nickel complexes trigger cell apoptosis, most likely due to cell cycle arrest. Interestingly, these complexes also inhibit androgen receptor (AR) and prostate-specific antigen (PSA) signaling, which are critical for prostate cancer survival and progression. Our study reveals a novel function of pincer nickel complexes as potential therapeutic drugs in prostate cancer.
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Berger, R., D. I. Lin, M. Nieto, S. Signoretti, W. C. Hahn, and M. Loda. "Androgen-dependent regulation of Her-2/neu in prostate cancer cells." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10099. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10099.
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10099 Background: The mechanisms underlying the progression of prostate cancer to androgen independence remain poorly understood. Overexpression of Her-2/neu (c-ErbB2) activates the androgen receptor pathway and confers a survival and growth advantage to prostate cancer cells in an androgen-deficient milieu. Methods: Androgen-sensitive prostate cancer cell line LNCaP was used as a model system in vitro and in vivo. Experiments in mice were undertaken by injecting cells orthotopically into the ventral lobe of the mice prostate. Results: Here, we report that androgen receptor (AR) and Her-2/neu reciprocally regulate each other in LNCaP human prostate cancer cells. Absence of androgens, AR blockade with Casodex (bicalutamide) or suppression of AR with RNAi induced Her-2/neu protein expression and phosphorylation in vitro and in vivo. Similarly, suppression of Her-2-neu expression resulted in AR upregulation. In contrast, upon re-administration of androgens, Her-2/neu mRNA, protein and phosphorylation levels decreased linearly with increasing concentrations of androgens as LNCaP cells re-entered the cell cycle. Conclusions: Thus, induction and activation of Her-2/neu occurs in an androgen-depleted environment or as a result of AR inactivation, promoting androgen-independent survival of prostate cancer cells. No significant financial relationships to disclose.
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Ali, Amaal, and George Kulik. "Signaling Pathways That Control Apoptosis in Prostate Cancer." Cancers 13, no. 5 (February 24, 2021): 937. http://dx.doi.org/10.3390/cancers13050937.
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Prostate cancer is the second most common malignancy and the fifth leading cancer-caused death in men worldwide. Therapies that target the androgen receptor axis induce apoptosis in normal prostates and provide temporary relief for advanced disease, yet prostate cancer that acquired androgen independence (so called castration-resistant prostate cancer, CRPC) invariably progresses to lethal disease. There is accumulating evidence that androgen receptor signaling do not regulate apoptosis and proliferation in prostate epithelial cells in a cell-autonomous fashion. Instead, androgen receptor activation in stroma compartments induces expression of unknown paracrine factors that maintain homeostasis of the prostate epithelium. This paradigm calls for new studies to identify paracrine factors and signaling pathways that control the survival of normal epithelial cells and to determine which apoptosis regulatory molecules are targeted by these pathways. This review summarizes the recent progress in understanding the mechanism of apoptosis induced by androgen ablation in prostate epithelial cells with emphasis on the roles of BCL-2 family proteins and “druggable” signaling pathways that control these proteins. A summary of the clinical trials of inhibitors of anti-apoptotic signaling pathways is also provided. Evidently, better knowledge of the apoptosis regulation in prostate epithelial cells is needed to understand mechanisms of androgen-independence and implement life-extending therapies for CRPC.
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Quiros-Gonzalez, Isabel, Rosa M. Sainz, David Hevia, and Juan C. Mayo. "MnSOD drives neuroendocrine differentiation, androgen independence, and cell survival in prostate cancer cells." Free Radical Biology and Medicine 50, no. 4 (February 2011): 525–36. http://dx.doi.org/10.1016/j.freeradbiomed.2010.10.715.
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Scafoglio, Claudio, Bruce A. Hirayama, Vladimir Kepe, Jie Liu, Chiara Ghezzi, Nagichettiar Satyamurthy, Neda A. Moatamed, et al. "Functional expression of sodium-glucose transporters in cancer." Proceedings of the National Academy of Sciences 112, no. 30 (July 13, 2015): E4111—E4119. http://dx.doi.org/10.1073/pnas.1511698112.
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Glucose is a major metabolic substrate required for cancer cell survival and growth. It is mainly imported into cells by facilitated glucose transporters (GLUTs). Here we demonstrate the importance of another glucose import system, the sodium-dependent glucose transporters (SGLTs), in pancreatic and prostate adenocarcinomas, and investigate their role in cancer cell survival. Three experimental approaches were used: (i) immunohistochemical mapping of SGLT1 and SGLT2 distribution in tumors; (ii) measurement of glucose uptake in fresh isolated tumors using an SGLT-specific radioactive glucose analog, α-methyl-4-deoxy-4-[18F]fluoro-d-glucopyranoside (Me4FDG), which is not transported by GLUTs; and (iii) measurement of in vivo SGLT activity in mouse models of pancreatic and prostate cancer using Me4FDG-PET imaging. We found that SGLT2 is functionally expressed in pancreatic and prostate adenocarcinomas, and provide evidence that SGLT2 inhibitors block glucose uptake and reduce tumor growth and survival in a xenograft model of pancreatic cancer. We suggest that Me4FDG-PET imaging may be used to diagnose and stage pancreatic and prostate cancers, and that SGLT2 inhibitors, currently in use for treating diabetes, may be useful for cancer therapy.
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Den, R. B., S. Ciment, A. Sharma, H. Mellert, S. Mc-Mahon, A. Dicker, and K. E. Knudsen. "Relationship between the loss of the retinoblastoma tumor suppressor and radiosensitivity." Journal of Clinical Oncology 29, no. 7_suppl (March 1, 2011): 34. http://dx.doi.org/10.1200/jco.2011.29.7_suppl.34.
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34 Background: Prostate cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in U.S. men. The retinoblastoma tumor suppressor protein, RB, plays a critical role in cell cycle regulation. Loss of RB has been observed in 25–30% of prostate cancers and is correlated with increasing tumor stage and grade. The clinical consequences of RB loss are unknown. We have previously shown that RB loss results in a castrate resistant phenotype. We hypothesized that RB loss would downregulate the G1-S cell cycle arrest normally induced by irradiation, inhibit DNA repair, and subsequently sensitize cells to mitotic catastrophe. Methods: Experimental work was performed with multiple isogenic prostate cancer cell lines (hormone sensitive: LNCaP and LAP-C4 cells and hormone resistant C42 cells; stable knockdown of RB using shRNA). Gamma H2AX assays were used to quantitate DNA damage and PARP cleavage and Caspase 3 were used to quantitate apoptosis. FACS analysis with BrdU was used to assess the cell cycle. Cell survival was measured using the clonogenic cell survival assay. In vivo work was performed in nude mice with tumor xenografts. Results: We observed that loss of RB increased radioresponsiveness in both transient and clonogenic cell survival assays in all cell lines (p<0.05). Cell death was not mediated through increased apoptosis, however, there was increased cell cycling despite the presence of DNA damage in the RB knockdown cells. In vivo xenografts of the RB deficient tumors exhibited diminished tumor mass, lower PSA kinetics and decreased tumor growth after treatment with single fraction of ionizing radiation in comparison to RB intact tumors (p<0.05). Conclusions: Loss of RB results in a differential response to ionizing radiation. Isogenic cells with RB knockdown are more sensitive to DNA damage and result in reduced cell survival. RB status is integral to determining which therapeutic modality should be employed in the management of prostate cancer. No significant financial relationships to disclose.
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Izumi, Kouji, and Atsushi Mizokami. "Suppressive Role of Androgen/Androgen Receptor Signaling via Chemokines on Prostate Cancer Cells." Journal of Clinical Medicine 8, no. 3 (March 13, 2019): 354. http://dx.doi.org/10.3390/jcm8030354.
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Androgen/androgen receptor (AR) signaling is a significant driver of prostate cancer progression, therefore androgen-deprivation therapy (ADT) is often used as a standard form of treatment for advanced and metastatic prostate cancer patients. However, after several years of ADT, prostate cancer progresses to castration-resistant prostate cancer (CRPC). Androgen/AR signaling is still considered an important factor for prostate cancer cell survival following CRPC progression, while recent studies have reported dichotomic roles for androgen/AR signaling. Androgen/AR signaling increases prostate cancer cell proliferation, while simultaneously inhibiting migration. As a result, ADT can induce prostate cancer metastasis. Several C-C motif ligand (CCL)-receptor (CCR) axes are involved in cancer cell migration related to blockade of androgen/AR signaling. The CCL2-CCR2 axis is negatively regulated by androgen/AR signaling, with the CCL22-CCR4 axis acting as a further downstream mediator, both of which promote prostate cancer cell migration. Furthermore, the CCL5-CCR5 axis inhibits androgen/AR signaling as an upstream mediator. CCL4 is involved in prostate carcinogenesis through macrophage AR signaling, while the CCL21-CCR7 axis in prostate cancer cells is activated by tumor necrotic factor, which is secreted when androgen/AR signaling is inhibited. Finally, the CCL2-CCR2 axis has recently been demonstrated to be a key contributor to cabazitaxel resistance in CRPC.
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Lopes, Nair, Mariana Brütt Pacheco, Diana Soares-Fernandes, Margareta P. Correia, Vânia Camilo, Rui Henrique, and Carmen Jerónimo. "Hydralazine and Enzalutamide: Synergistic Partners against Prostate Cancer." Biomedicines 9, no. 8 (August 7, 2021): 976. http://dx.doi.org/10.3390/biomedicines9080976.
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Advanced prostate cancers frequently develop resistance to androgen-deprivation therapy with serious implications for patient survival. Considering their importance in this type of neoplasia, epigenetic modifications have drawn attention as alternative treatment strategies. The aim of this study was to assess the antitumoral effects of the combination of hydralazine, a DNA methylation inhibitor, with enzalutamide, an antagonist of the androgen receptor, in prostate cancer cell lines. Several biological parameters, such as cell viability, proliferation, DNA damage, and apoptosis, as well as clonogenic and invasive potential, were evaluated. The individual treatments with hydralazine and enzalutamide exerted growth-inhibitory effects in prostate cancer cells and their combined treatment displayed synergistic effects. The combination of these two drugs was very effective in decreasing malignant features of prostate cancer and may become an alternative therapeutic option for prostate cancer patient management.
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Loberg, Robert D., Christopher J. Logothetis, Evan T. Keller, and Kenneth J. Pienta. "Pathogenesis and Treatment of Prostate Cancer Bone Metastases: Targeting the Lethal Phenotype." Journal of Clinical Oncology 23, no. 32 (November 10, 2005): 8232–41. http://dx.doi.org/10.1200/jco.2005.03.0841.
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Traditionally, prostate cancer treatment, as well as all cancer treatment, has been designed to target the tumor cell directly via various hormonal and chemotherapeutic agents. Recently, the realization that cancer cells exist in complex microenvironments that are essential for the tumorigenic and metastatic potential of the cancer cells is starting the redefine the paradigm for cancer therapy. The propensity of prostate cancer cells to metastasize to bone is leading to the design of novel therapies targeting both the cancer cell as well as the bone microenvironment. Tumor cells in the bone interact with the extracellular matrix, stromal cells, osteoblasts, osteoclasts, and endothelial cells to promote tumor-cell survival and proliferation leading to a lethal phenotype that includes increased morbidity and mortality for patients with advanced prostate cancer. Several strategies are being developed that target these complex tumor cell–microenvironment interactions and target the signal transduction pathways of other cells important to the development of metastases, including the osteoclasts, osteoblasts, and endothelial cells of the bone microenvironment. Current and new therapies in metastatic prostate cancer will comprise a multitargeted approach aimed at both the tumor cell and the tumor microenvironment. Here, we review the current therapeutic strategies for targeting the prostate cancer–bone microenvironment and several single- and multiagent targeted approaches to the treatment of advanced prostate cancer that are under development.
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Zhang, Ruochen, Yaojing Yang, Haijian Huang, Tao Li, Liefu Ye, Le Lin, and Yongbao Wei. "UBC Mediated by SEPT6 Inhibited the Progression of Prostate Cancer." Mediators of Inflammation 2021 (December 20, 2021): 1–12. http://dx.doi.org/10.1155/2021/7393029.
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Background. Prostate cancer is one of the most common malignancies in men. Protein ubiquitination is an important mechanism for regulating protein activity and level in vivo. We aimed to study the mechanism of SEPT6 and UBC action in prostate cancer to identify new targets. Methods. The ubiquitin-protein and the ubiquitin coding gene UBA52, UBA80, UBB, and UBC expressions were detected in clinical tissues and cells. Overexpression and knockdown of UBC were performed in prostate cancer DU145 cells. Cell Counting Kit 8 (CCK-8) assay was performed to detect cell proliferation. Cell cycle at 24 h was detected by flow cytometry. Clonal formation assay was used to measure cell clone number. Immunofluorescence (IF) was performed to detect the colocalization of SEPT6 and UBC in prostate cancer cells. Next, we overexpressed or knocked down SEPT6 expression in DU145 cells. Pearson correlation coefficient was applied to analyze the relationship between SEPT6 and UBC in prostate cancer tissue. oe-SEPT6+oe-UBC coexpressing cells were constructed to detect the upstream and downstream relationship between SEPT6 and UBC on prostate cancer cells. The tumor formation experiment was performed to explore SEPT6/UBC effect on prostate cancer. Results. UBC was upregulated in prostate cancer tissues and cells. Overexpression of UBC promoted cell survival and proliferation. IF revealed the colocalization of SEPT6 and UBC in prostate cancer cells. UBC expression decreased after oe-SEPT6, while increased after sh-SEPT6, indicating that UBC was downstream of SEPT6. Pearson correlation coefficient analysis showed that SEPT6 was negatively correlated with UBC in prostate cancer tissues. SEPT6 as an upstream gene of UBC regulated prostate cancer cell behavior through UBC. The tumor formation experiment showed that SEPT6 could inhibit tumor growth. Conclusion. In general, SEPT6 inhibited UBC expression, thereby reducing the overall ubiquitination level, affecting the expression level of downstream cell proliferation-related genes, and then affecting the progression of prostate cancer.
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Samiea, Abrar, Jeff S. J. Yoon, Christopher J. Ong, Amina Zoubeidi, Thomas C. Chamberlain, and Alice L. F. Mui. "Interleukin-10 Induces Expression of Neuroendocrine Markers and PDL1 in Prostate Cancer Cells." Prostate Cancer 2020 (July 31, 2020): 1–12. http://dx.doi.org/10.1155/2020/5305306.
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Interleukin-10 (IL10) is best studied for its inhibitory action on immune cells and ability to suppress an antitumour immune response. But IL10 also exerts direct effects on nonimmune cells such as prostate cancer epithelial cells. Elevated serum levels of IL10 observed in prostate and other cancer patients are associated with poor prognosis. After first-line androgen-deprivation therapy, prostate cancer patients are treated with androgen receptor antagonists such as enzalutamide to inhibit androgen-dependent prostate cancer cell growth. However, development of resistance inevitably occurs and this is associated with tumour differentiation to more aggressive forms such as a neuroendocrine phenotype characterized by expression of neuron specific enolase and synaptophysin. We found that treatment of prostate cancer cell lines in vitro with IL10 or enzalutamide induced markers of neuroendocrine differentiation and inhibited androgen receptor reporter activity. Both also upregulated the levels of PDL1, which could promote tumour survival in vivo through its interaction with the immune cell inhibitory receptor PD1 to suppress antitumour immunity. These findings suggest that IL10’s direct action on prostate cancer cells could contribute to prostate cancer progression independent of IL10’s suppression of host immune cells.
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Li, Pengfei, Heehyoung Lee, Shaodong Guo, Terry G. Unterman, Guido Jenster, and Wenlong Bai. "AKT-Independent Protection of Prostate Cancer Cells from Apoptosis Mediated through Complex Formation between the Androgen Receptor and FKHR." Molecular and Cellular Biology 23, no. 1 (January 1, 2003): 104–18. http://dx.doi.org/10.1128/mcb.23.1.104-118.2003.
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ABSTRACT Recent studies suggested that the protection of cell apoptosis by AKT involves phosphorylation and inhibition of FKHR and related FOXO forkhead transcription factors and that androgens provide an AKT-independent cell survival signal in prostate cancer cells. Here, we report receptor-dependent repression of FKHR function by androgens in prostate cancer cells. Transcriptional analysis demonstrated that activation of the androgen receptor caused an inhibition of both wild-type FKHR and a mutant in which all three known AKT sites were mutated to alanines, showing that the repression is AKT independent. In vivo and in vitro coprecipitation studies demonstrated that the repression is mediated through protein-protein interaction between FKHR and the androgen receptor. Mapping analysis localized the interacting domains to the carboxyl terminus between amino acids 350 and 655 of FKHR and to the amino-terminal A/B region and the ligand binding domain of the receptor. Further analysis demonstrated that the activated androgen receptor blocked FKHR's DNA binding activity and impaired its ability to induce Fas ligand expression and prostate cancer cell apoptosis and cell cycle arrest. These studies identify a new mechanism for androgen-mediated prostate cancer cell survival that appears to be independent of the activity of the receptor on androgen response element-mediated transcription and establish FKHR and related FOXO forkhead proteins as important nuclear targets for both AKT-dependent and -independent survival signals in prostate cancer cells.
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Akova Ölken, Elif, Attila Aszodi, Hanna Taipaleenmäki, Hiroaki Saito, Veronika Schönitzer, Michael Chaloupka, Maria Apfelbeck, Wolfgang Böcker, and Maximilian Michael Saller. "SFRP2 Overexpression Induces an Osteoblast-like Phenotype in Prostate Cancer Cells." Cells 11, no. 24 (December 16, 2022): 4081. http://dx.doi.org/10.3390/cells11244081.
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Prostate cancer bone metastasis is still one of the most fatal cancer diagnoses for men. Survival of the circulating prostate tumor cells and their adaptation strategy to survive in the bone niche is the key point to determining metastasis in early cancer stages. The promoter of SFRP2 gene, encoding a WNT signaling modulator, is hypermethylated in many cancer types including prostate cancer. Moreover, SFRP2 can positively regulate osteogenic differentiation in vitro and in vivo. Here, we showed SFRP2 overexpression in the prostate cancer cell line PC3 induces an epithelial mesenchymal transition (EMT), increases the attachment, and modifies the transcriptome towards an osteoblast-like phenotype (osteomimicry) in a collagen 1-dependent manner. Our data reflect a novel molecular mechanism concerning how metastasizing prostate cancer cells might increase their chance to survive within bone tissue.
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Peng, Nai-Xiong, Chun-Xiao Liu, Xi-Sheng Wang, Ze-Jian Zhang, and Su-Cai Liao. "Combination of axitinib and dasatinib for anti-cancer activities in two prostate cancer cell lines." Bangladesh Journal of Pharmacology 11, no. 1 (December 25, 2015): 130. http://dx.doi.org/10.3329/bjp.v11i1.24149.
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<p class="Abstract">Prostate cancer is major cause of cancer related deaths worldwide in men. There are new treatment methods and drugs are being developed with promising results in two of the prostate cancer cell lines (PPC-1 and TSU-Pr1). These two cells were treated with 20 uM of axitinib combined with dasatinib for 6-72 hours. The cell viability assessed by the cytotoxicity assay. Various regulatory genes such as c-KIT, cell cycle and apoptosis and angiogenic factors were also studied. The enzyme activity of apoptosis efector caspase-3 was colorimetrically determined. Axitinib and dasatinib combination lowered the survival rate of PPC-1 cells but enhanced the survival rate of TSU-Pr1 cells. The protein expression levels in apoptosis and angiogenesis factors were also found to be in contrast between the two cell lines. PPC-1 and TSU-Pr1 cells displayed a different response to axitinib with dasatinib, which explains different expression levels of regulators of cell-cycle, apoptosis and angiogenesis.</p><p> </p>
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Luo, Gang, Miao Wang, Xinchao Wu, Dan Tao, Xinyuan Xiao, Liang Wang, Fan Min, Fuqing Zeng, and Guosong Jiang. "Long Non-Coding RNA MEG3 Inhibits Cell Proliferation and Induces Apoptosis in Prostate Cancer." Cellular Physiology and Biochemistry 37, no. 6 (2015): 2209–20. http://dx.doi.org/10.1159/000438577.
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Background/Aims: Long non-coding RNAs (lncRNAs) play important roles in diverse biological processes, such as cell growth, apoptosis and migration. Although downregulation of lncRNA maternally expressed gene 3 (MEG3) has been identified in several cancers, little is known about its role in prostate cancer progression. The aim of this study was to detect MEG3 expression in clinical prostate cancer tissues, investigate its biological functions in the development of prostate cancer and the underlying mechanism. Methods: MEG3 expression levels were detected by qRT-PCR in both tumor tissues and adjacent non-tumor tissues from 21 prostate cancer patients. The effects of MEG3 on PC3 and DU145 cells were assessed by MTT assay, colony formation assay, western blot and flow cytometry. Transfected PC3 cells were transplanted into nude mice, and the tumor growth curves were determined. Results: MEG3 decreased significantly in prostate cancer tissues relative to adjacent normal tissues. MEG3 inhibited intrinsic cell survival pathway in vitro and in vivo by reducing the protein expression of Bcl-2, enhancing Bax and activating caspase 3. We further demonstrated that MEG3 inhibited the expression of cell cycle regulatory protein Cyclin D1 and induced cell cycle arrest in G0/G1 phase. Conclusions: Our study presents an important role of MEG3 in the molecular etiology of prostate cancer and implicates the potential application of MEG3 in prostate cancer therapy.
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Han, Bin, Naohiro Fujimoto, Mizuki Kobayashi, and Tetsuro Matsumoto. "Synergistic Effect of Geranylgeranyltransferase Inhibitor, GGTI, and Docetaxel on the Growth of Prostate Cancer Cells." Prostate Cancer 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/989214.
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Most advanced prostate cancers progress to castration resistant prostate cancer (CRPC) after a few years of androgen deprivation therapy and the prognosis of patients with CRPC is poor. Although docetaxel and cabazitaxel can prolong the survival of patients with CRPC, inevitable progression appears following those treatments. It is urgently required to identify better or alternative therapeutic strategies. The purpose of this study was to confirm the anti-cancer activity of zoledronic acid (Zol) and determine whether inhibition of geranylgeranylation in the mevalonate pathway could be a molecular target of prostate cancer treatment. We examined the growth inhibitory effect of Zol in prostate cancer cells (LNCaP, PC3, DU145) and investigated a role of geranylgeranylation in the anticancer activity of Zol. We, then, evaluated the growth inhibitory effect of geranylgeranyltransferase inhibitor (GGTI), and analyzed the synergy of GGTI and docetaxel by combination index and isobolographic analysis. Zol inhibited the growth of all prostate cancer cell lines tested in a dose-dependent manner through inhibition of geranylgeranylation. GGTI also inhibited the prostate cancer cell growth and the growth inhibitory effect was augmented by a combination with docetaxel. Synergism between GGTI and docetaxel was observed across a broad range of concentrations. In conclusion, our results demonstrated that GGTI can inhibit the growth of prostate cancer cells and has synergistic effect with docetaxel, suggesting its potential role in prostate cancer treatment.
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Dagvadorj, Ayush, Sean Collins, Jean-Baptiste Jomain, Junaid Abdulghani, James Karras, Tobias Zellweger, Hongzhen Li, et al. "Autocrine Prolactin Promotes Prostate Cancer Cell Growth via Janus Kinase-2-Signal Transducer and Activator of Transcription-5a/b Signaling Pathway." Endocrinology 148, no. 7 (July 1, 2007): 3089–101. http://dx.doi.org/10.1210/en.2006-1761.
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The molecular mechanisms that promote progression of localized prostate cancer to hormone-refractory and disseminated disease are poorly understood. Prolactin (Prl) is a local growth factor produced in high-grade prostate cancer, and exogenously added Prl in tissue or explant cultures of normal and malignant prostate is a strong mitogen and survival factor for prostate epithelium. The key signaling proteins that mediate the biological effects of Prl in prostate cancer are Signal Transducer and Activator of Transcription (Stat)-5a/5b via activation of Janus kinase-2. Importantly, inhibition of Stat5a/b in prostate cancer cells induces apoptotic death. Using a specific Prl receptor antagonist (Δ1–9G129R-hPRL), we demonstrate here for the first time that autocrine Prl in androgen-independent human prostate cancer cells promotes cell viability via Stat5 signaling pathway. Furthermore, we examined a unique clinical material of human hormone refractory prostate cancers and metastases and show that autocrine Prl is expressed in 54% of hormone-refractory clinical human prostate cancers and 62% prostate cancer metastases. Finally, we demonstrate that autocrine Prl is expressed from both the proximal and distal promoters of the Prl gene in clinical human prostate cancers and in vivo and in vitro human prostate cancer models, independently of pituitary transcription factor-1 (Pit-1). Collectively, the data provide novel evidence for the concept that autocrine Prl signaling pathway is involved in growth of hormone-refractory and metastatic prostate cancer. The study also provides support for the use of Prl receptor antagonists or other therapeutic strategies to block the Prl-Janus kinase-2-Stat5 signaling pathway in advanced prostate cancer.
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Lin, Yi-Chia, Po-Cheng Liao, Te-Fu Tsai, Kuang-Yu Chou, Hung-En Chen, Ji-Fan Lin, and Thomas I.-Sheng Hwang. "Zoledronic Acid Elicits Proinflammatory Cytokine Profile in Osteolytic Prostate Cancer Cells." ISRN Pathology 2014 (April 23, 2014): 1–8. http://dx.doi.org/10.1155/2014/124746.
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Zoledronic acid (ZA), a bisphosphonate used to prevent skeletal fractures in patients with cancers, was demonstrated to induce apoptosis in a number of cancer cells. Our previous study showed that ZA also induces autophagic cell death in metastatic prostate cancer cells. However, the clinical trials using ZA in the treatment of metastatic prostate cancer did not have a longer diseases-free period. Since most of ZA was attracted to the bone after administration, we hypothesized that local prostate cancer cells may evolve prosurvival pathways upon low concentration of ZA treatment. In this study, we investigated the inflammatory effects of ZA on osteolytic PC3 prostate cancer cell, since inflammation was reported to be related to cancer development and survival. Exposure of PC3 cells to various concentrations of ZA resulted in induction of apoptosis and autophagy. The expression of inflammatory biomarkers including interleukin 6 (IL-6), cyclooxygenase-2 (COX-2), and NF-κB was remarkably upregulated in response to ZA treatment in a dose- and time-dependent manner. The production of IL-6 was elevated upon ZA treatment. The antiapoptotic protein Bcl2 was increased with parallel increased level of IL-6. Our data suggest that treatment with low concentrations of ZA enhances the inflammatory profile and may serve as a prosurvival signaling pathway in PC3 cells.
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Jia, Wenqiao, Pengxiang Chen, and Yufeng Cheng. "PRDX4 and Its Roles in Various Cancers." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381986431. http://dx.doi.org/10.1177/1533033819864313.
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Reactive oxygen species play a vital role in cell survival by regulating physiological metabolism and signal transduction of cells. The imbalance of oxidant and antioxidant states induces oxidative stress within a cell. Redox regulation and oxidative stress are closely related to survival and proliferation of stem cells, cancer cells, and cancer stem cells. Peroxiredoxin 4, a typical endoplasmic reticulum-resident 2-Cys antioxidant of peroxiredoxins, can fine-tune hydrogen peroxide catabolism which affects cell survival by affecting redox balance, oxidative protein folding, and regulation of hydrogen peroxide signaling. Recent studies revealed the overexpression of peroxiredoxin 4 in several kinds of cancers, such as breast cancer, prostate cancer, ovarian cancer, colorectal cancer, and lung cancer. And it has been demonstrated that peroxiredoxin 4 causally contributes to tumorigenesis, therapeutic resistance, metastasis, and recurrence of tumors. In this article, the characteristics of peroxiredoxin 4 in physiological functions and the cancer-related research progress of mammalian peroxiredoxin 4 is reviewed. We believe that peroxiredoxin 4 has the potential of serving as a novel target for multiple cancers.
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Shain, Sydney A. "Exogenous Fibroblast Growth Factors Maintain Viability, Promote Proliferation, and Suppress GADD45α and GAS6 Transcript Content of Prostate Cancer Cells Genetically Modified to Lack Endogenous FGF-2." Molecular Cancer Research 2, no. 11 (November 1, 2004): 653–61. http://dx.doi.org/10.1158/1541-7786.653.2.11.
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Abstract Understanding processes regulating prostate cancer cell survival is critical to management of advanced disease. We used prostate cancer cell transfectants genetically modified to be deficient in either endogenous fibroblast growth factor (FGF-1) or endogenous FGF-2 to examine FGF maintenance of transfectant survival and proliferation and FGF-2-regulated expression of transfectant growth arrest DNA damage (GADD) and growth arrest sequences (GAS) family genes (known modulators of cell cycle progression and survival) and the AS3 gene (an androgen-modulated effector of prostate cell proliferation). When propagated in the absence of exogenous FGFs, FGF-2-deficient transfectants undergo exponential death, whereas FGF-1-deficient transfectants proliferate. Exogenous FGF-1, FGF-2, FGF-7, or FGF-8 promote survival and proliferation of FGF-2-deficient transfectants and enhance FGF-1-deficient transfectant proliferation. Transfectants express FGF receptor FGFR1, FGFR2(IIIb), FGFR2(IIIc), and FGFR3 transcripts, findings consistent with the effects of exogenous FGFs. FGF-2-deficient transfectants express high levels of AS3, GADD45α, GADD45γ, GAS8, and GAS11 transcripts and moderate levels of GADD153, GAS2, GAS3, and GAS6 transcripts and lack demonstrable GAS1 or GAS5 transcripts. FGF withdrawal-mediated death of FGF-2-deficient transfectants did not significantly affect cell AS3, GADD153, GADD45γ, GAS2, GAS3, GAS7, GAS8, or GAS11 transcript content, whereas GADD45α and GAS6 transcript content was elevated. These studies establish that endogenous FGF-2 dominantly regulates prostate cancer cell survival and proliferation and that exogenous FGFs may assume this function in the absence of endogenous FGF-2. Additionally, we provide the first evidence that FGFs regulate prostate GADD45α and GAS6 transcript content. The latter observations suggest that GADD45α and GAS6 proteins may be effectors of processes that regulate prostate cancer cell survival. Additional studies are required to examine this possibility in detail.
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Amato, Robert J., Vladislava O. Melnikova, Yujian Zhang, Wen Liu, Yuan Wang, Parth K. Shah, Brett T. Jensen, Karen E. Torres, and Darren W. Davis. "Correlation of circulating tumor cells (CTCs) and clinical biomarker endpoints in metastatic prostate cancer patients." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e15124-e15124. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e15124.
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e15124 Background: Circulating tumor cells (CTCs) are found in human blood when cancers undergo metastatic dissemination, and CTCs have been reported as a surrogate marker for tumor response and linked to shorter survival in metastatic prostate cancer patients. This study assessed the use of CTCs as a continuous factor for clinical monitoring of prostate cancers patient in real time and evaluated the association between baseline CTC number, various clinical characteristics, and survival. Methods: CTCs were enumerated using the CellSearch FDA cleared CTC kit in 206 patients with metastatic prostate cancer. Variables including metastatic site, PSA, Gleason score, level of testosterone and androgen treatment were tested for association with CTC number. The probability of patient survival over time was estimated by the Kaplan-Meier method. Results: Baseline CTC numbers were strongly associated with survival (p<0.0001), with overall survival being significantly poorer in patients with ≥5 CTCs. Significantly higher CTC numbers were observed in patients with bone metastasis (mean=41.1 CTCs) compared to those with lymph node metastasis (mean=2.5 CTC, p=0.026). Analysis of the association between CTC counts and PSA level revealed a weak positive correlation between CTC number and PSA (Correlation coefficient r=0.269, Significance level p<0.001). CTC number further correlated with the Gleason score (p=0.009) and lower testosterone levels (p<0.0001). Patients with no androgen depletion had significantly lower numbers of CTCs (median=3.94) compared to those with androgen depletion (median=406, p<0.001). Conclusions: Baseline CTCs are predictive of patient survival and are significantly correlated with clinical characteristics in prostate cancer patients.Our study confirms previous findings that support the use of CTC levels as a prognostic biomarker for prostate cancer patients.